Individual data from 1072 participants from five randomised controlled
trials were obtained. More individuals treated with lamotrigine than placebo
responded to treatment on both the Hamilton Rating Scale for Depression (HRSD)
(relative risk (RR)=1.27, 95% CI 1.09–1.47, P=0.002) and
Montgomery–Åsberg Depression Rating Scale (MADRS) (RR=1.22, 95% CI
1.06–1.41, P=0.005). There was an interaction (P=0.04)
by baseline severity of depression: lamotrigine was superior to placebo in
people with HRSD score >24 (RR=1.47, 95% CI 1.16–1.87,
P=0.001) but not in people with HRSD score ≤24 (RR=1.07, 95% CI
0.90–1.27, P=0.445).

Conclusions

There is consistent evidence that lamotrigine has a beneficial effect on
depressive symptoms in the depressed phase of bipolar disorder. The overall
pool effect was modest, although the advantage over placebo was larger in more
severely depressed participants.

Bipolar disorder is among the top causes of worldwide disability and is
characterised by both depressive and manic
episodes.1 The
depressive symptoms are now recognised to be the predominant cause of
disability in the long term for most people with bipolar
disorder.2–4
Prior to 1999, the treatment of bipolar depression had been little studied and
there was uncertainty about the treatment of this phase of the disorder. There
have long been concerns about the risk of mood destabilisation with
antidepressant drugs and there remains uncertainty about efficacy. A
meta-analysis found some evidence for
efficacy5 but a
subsequent large trial conducted as part of the National Institute of Mental
Health funded Systematic Treatment Enhancement Program for Bipolar Disorder
(NIMH STEP–BD) found no evidence of benefit for adjunctive therapy with
bupropion or
paroxetine.6

Recent guidelines have suggested a role for lamotrigine, an inhibitor of
voltage-sensitive sodium channels in the acute treatment of bipolar
depression. Lamotrigine is only licensed in the USA by the Food and Drug
Administration and in some European countries for prevention of relapse in
bipolar disorder.7
None the less, it is already in common clinical use for bipolar disorder,
particularly in the
USA.8 Although the
evidence for the long-term efficacy of lamotrigine is reasonably robust, the
five pivotal trials in acute phase therapy have been reported as individually
neutral, with no statistically significant benefit from
lamotrigine.9 This
apparent lack of acute efficacy sits rather uncomfortably beside evidence for
efficacy for relapse prevention. Although lamotrigine may indeed be
ineffective in the acute phase, it is possible that the therapeutic effect
size of lamotrigine may be smaller than predicted and that the acute trials
were consequently underpowered. It is also possible that the need to increase
the dose of lamotrigine gradually may have made detection of the acute
therapeutic effect more difficult or that any positive effects are confined to
a subgroup of individuals and not observable in the full trial samples.

Meta-analysis can increase the statistical power for analysis of the
available randomised data. Data can be combined in a variety of ways: pooling
individual participant data from several trials is the most informative for
meta-analysis because it allows investigation of potential differential
effects across participant
subgroups.10,11
We report a meta-analysis of the individual participant data from the five
trials conducted by GlaxoSmithKline investigating the efficacy of lamotrigine
in acute bipolar depression.

Method

Inclusion criteria

We included all the randomised controlled trials conducted by
GlaxoSmithKline comparing lamotrigine with placebo in bipolar depression
(online Table DS1 and Table
1).

Search strategy

Data analysis

Individual patient data-sets were compiled from the five
GlaxoSmithKline-sponsored trials comparing lamotrigine with placebo. Analyses
were of the full intention-to-treat trial populations. The last available
observation was used for participants who withdrew from the trial before the
end of the study. The a priori data analysis plan included analyses
of both categorical and continuous outcomes. Trial-specific estimates of the
relative risks of response (>50% reduction in baseline score on Hamilton
Rating Scale for
Depression13 (HRSD)
and Montgomery–Åsberg Depression Rating
Scale14 (MADRS))
and remission (<8 on HRSD and <12 on MADRS) were calculated and pooled
using the Mantel–Haenszel fixed effect approach in metan in STATA
version 9. The number needed to treat (NNT) was estimated from the inverse of
the weighted mean absolute difference in event rates. For continuous measures,
separate ANCOVA analyses were conducted of final score (adjusted for baseline)
and then pooled using metan.

A planned subgroup analysis was conducted to investigate whether the
treatment effect differed between (a) individuals with bipolar I and bipolar
II disorder and (b) individuals with severe depressive illness and moderate
illness at randomisation. As there is no universally accepted cut point for
the HRSD,15 we
dichotomised the sample around the mean baseline score in the trials. We used
meta-regression for the subgroup analysis which is a method that allows the
investigation of whether any particular covariates are related to the observed
study-specific treatment
effects.16 In
STATA, the metareg command uses a random effects iterative method to provide a
restricted maximum likelihood estimate of the regression parameters (with
their asymptotic variances) and the residual heterogeneity
variance.17
Meta-regression can be a powerful technique but its use in aggregated data is
limited to the investigation of study-level variables. The use of individual
patient data allows more informative meta-regression analyses of trial data
because precisely defined subgroup analyses can be conducted applying
consistent definitions across trials.

Discontinuation rates

As a measure of overall acceptability, discontinuation rates from the study
arms were compared in each trial using relative risks and pooled using the
Mantel–Haenszel fixed effect approach in metan in STATA version 9.

Results

There were five randomised controlled trials (total 1072 participants)
conducted by GlaxoSmithKline to compare lamotrigine with placebo in bipolar
disorder. Summary details of the trials are presented in online Table DS1 and
Table 1, and are reported in
detail elsewhere.9
All five trials compared lamotrigine monotherapy with placebo. Individuals
were only included if they had discontinued any other psychoactive drug at
least five elimination half-lives before trial entry. Prior treatment with
lamotrigine was an exclusion criterion in all trials. Three trials
(GW602/SCAB2001, SCA40910, SCA30924) included only people with bipolar I
disorder, one trial (SCA10022) included only people with bipolar II disorder
and one trial (GW603/SCAA2010) included people with both bipolar I and II
disorder. Duration of the trial varied from 7 to 10 weeks. Lamotrigine dose
was 50 mg or 200 mg in GW602/SCAB2001, flexible 100–400 mg in
GW603/SCAA2010 and 200 mg in SCA40910, SCA30924 and SCA10022. After the
initial result from GW602/SCAB2001, the 50 mg dose was considered too low and
so was not included in the other trials. We did not therefore include the 50
mg arm in the meta-analysis.

Two non-GlaxoSmithKline sponsored trials were also
identified.18,19
As individual patient-level data were not available from these trials, and the
protocols differed substantially from the GlaxoSmithKline trials, these were
not included in the main analysis. Both trials, however, reported substantial
and statistically significant benefits with lamotrigine compared with placebo;
in one case, in combination with
lithium.17

In the severe group, the response to lamotrigine rate was 110/242 (45.5%)
compared with 71/236 (30.1%) in the placebo group. In the moderate group, the
response to lamotrigine rate was 142/299 (47.5%) compared with 131/294 (44.6%)
in the placebo group. Thus, the interaction by severity was because of a
higher response rate in the moderately ill placebo-treated group, rather than,
for example, a higher response rate in the severely ill lamotrigine-treated
group.

Discussion

Meta-analysis of the individual patient data from five
manufacturer-sponsored randomised trials found consistent evidence of an
overall modest benefit for lamotrigine. About 11 people would need to be
treated to achieve one more response than would be achieved on placebo: this
is at the margins of being clinically worthwhile. The magnitude of the
treatment effect in the main analysis was reduced by the high placebo response
rate in the moderately ill subgroup of participants. Consequently, the
treatment effect appears to be more substantial in participants who are more
severely ill (NNT=7) but the actual response rate on lamotrigine is very
similar in both subgroups.

As with all quantitative reviews, this review is subject to a number of
limitations. Publication bias, or the tendency for trials with negative or
neutral findings not to be published, can seriously limit the reliability of
meta-analysis. Moreover, studies from which individual data can be obtained
may not represent an unbiased sample of all the trials. In this analysis, the
bipolar depression trials included in the main analysis are the total of the
acute studies conducted by GlaxoSmithKline, the manufacturer of lamotrigine.
There is some evidence that trials conducted by the manufacturer of a drug may
be more likely to detect and report results that favour their
drug,20 but this is
not the case here. Indeed, our search revealed two
trials18,19
conducted independently of GlaxoSmithKline that both reported substantial
benefits with lamotrigine compared with placebo in acute bipolar depression.
This probably increases the confidence that we can have in the overall
results.

This review was highly focused on the effect of lamotrigine on depressive
symptoms and we did not request access to data on specific adverse events.
Withdrawal rates were similar for participants allocated to lamotrigine and
placebo. A comprehensive analysis of the rates of adverse events in these
trials has been recently
published.9 The most
common adverse events were headache and
nausea.9 The
incidence of non-serious rash was low and there were no reports of serious
rash in any of the five trials.

The finding of an interaction between the severity of depressive symptoms
at randomisation and the size of the treatment effect appeared to be because
of a larger placebo response in individuals who are less severely ill. This
suggests that the finding should be interpreted cautiously clinically as it
probably does not mean that only people who are severely ill are likely to
respond to lamotrigine. The finding is, however, of considerable
methodological importance, especially for the design of placebo-controlled
monotherapy trials. Although there is still some consensus that
placebo-controlled trials are required for regulatory
purposes,21 a
number of artefacts and biases (such as inflation of baseline scores to meet
eligibility criteria) can result from the difficulties of conducting
placebo-controlled trials when existing standard treatments are
available.15,22
These problems can inflate placebo response making it difficult to detect drug
effects but they are often overlooked in the interpretation of the results of
such trials. We believe that our results suggest that it is essential to
ensure a reliable and sufficient severity of illness at baseline in
participants in clinical trials to minimise such artefacts. This
methodological challenge is likely to increase in importance because the
increasing number of drugs for which an indication for bipolar disorder is
being sought has made recruitment of more participants who are severely ill
into placebo-controlled trials in bipolar disorder more
difficult.23
Although placebo control remains a regulatory requirement for the development
of new antidepressants, an adequate severity of symptoms at the point of
randomisation will remain a challenging prerequisite for success.

There was no difference in response to lamotrigine between bipolar disorder
type I and II subgroups. This parallels the findings in the BOLDER (BipOLar
DepRession) trials of
quetiapine,24,25
and supports the idea that depressive episodes arising in an illness course
characterised by mania or hypomania are probably very similar in terms of
treatment response.

The effect of lamotrigine compared with placebo only became statistically
significant when data from five randomised controlled trials were pooled by
meta-analysis. This might mean that the true effect of lamotrigine is too
small to be reliably detected by individual studies and, possibly, too small
to be clinically important. However, the interaction by baseline severity
suggests that the trial may actually have underestimated the true efficacy of
lamotrigine. It is worth noting that a simple ‘vote counting’
analysis (as is often used by regulatory authorities) would fail to quantify
the treatment effect at all. None of the individual trials reported a
statistically significant effect on the primary
outcome:9 this
meta-analysis suggests that there is a modest but consistent effect across the
trials. The current regulatory approach of requiring two ‘
successful’ pivotal trials may encourage the conduct of multiple,
underpowered trials. Conversely, there may be an unjustified focus on
unrepresentatively large effects from one or two trials that meet criteria for
statistical significance, ignoring (and failing to publish) any trials that do
not produce a statistically significant
result.26,27
The vote-counting approach does not make the most efficient or reliable use of
the total randomised data and routinely risks bias in the estimation of true
treatment effects. In this case, vote counting would have failed to detect a
positive treatment effect of uncertain clinical significance.

Finally, in addition to their clear methodological importance, the results
of this meta-analysis are potentially of clinical importance for people with
bipolar disorder and their doctors because they provide some solid empirical
support for a commonly used drug treatment in a disorder with few proven
therapies. It suggests that lamotrigine may be an effective treatment for
acute bipolar depression arising in a bipolar disorder of type I or II as well
as for prevention of relapse. Further trials are warranted to clarify the size
of the treatment effect of lamotrigine both as monotherapy and in combination:
the ongoing CEQUEL (Comparative Evaluation of QUEtiapine–Lamotrigine
combination v. quetiapine monotherapy (and folic acid v.
placebo) in people with bipolar depression) trial will provide further
knowledge of the effectiveness of lamotrigine as add-on therapy to quetiapine
in ‘real world’ people with bipolar disorder
(www.cequel.org).

Acknowledgments

The randomised trials included in this analysis were conducted and funded
by GlaxoSmithKline, who provided raw data-sets for independent analysis by the
authors. J.R.G. had full access to all of the data in the study and takes
responsibility for the integrity of the data and the accuracy of the data
analysis. This analysis was initiated entirely by the authors. No additional
support, either scientific or pecuniary, was provided by GlaxoSmithKline. We
are grateful to Walter Paska and Gary Evoniuk of GlaxoSmithKline for their
assistance in accessing the individual patient data and for their comments on
a draft of the manuscript. We are grateful to Ly-mee Yu and Will Stevens of
the Oxford Clinical Trial Unit for Mental Illness for help with the analyses
of the continuous data and data processing, and Sarah Stockton of the Centre
for Evidence-Based Mental Health for designing and implementing the search
strategy.

National Collaborating Centre for Mental Health. Depression:
Management of Depression in Primary and Secondary Care. National
Institute for Health and Clinical Excellence, 2004
(http://www.nice.org.uk/page.aspx?o=235213).